ES2939744T3 - Biodegradable Drug Release Compositions - Google Patents

Abstract

A biodegradable composition for drug delivery is described, comprising a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as a pharmaceutically active ingredient. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

Biodegradable Drug Release Compositions

field of invention

The present invention relates to biodegradable drug release compositions comprising a triblock copolymer containing a polyester, and a polyethylene glycol and a diblock copolymer containing a polyester, and an end-capped polyethylene glycol, as well as a pharmaceutically active ingredient. . The ratio of triblock copolymer to diblock copolymer in this formulation is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19. Methods for producing these biodegradable drug compositions using organic solvents are also disclosed.

Background of the present invention

Drug delivery systems such as diblock and triblock copolymers have been used to deliver a variety of drugs and are generally formulated to deliver specific drugs whether they are hydrophobic or hydrophilic drugs. Depending on the solubility of the drug these drug formulations differ in polymer concentrations, types of polymers used, molecular weights of the polymers, and solvents used in the formulations.

The type of environment in which the drug is administered is also an important consideration in the formulation of a drug delivery system. Therefore, there are drug delivery compositions that are prepared using temperature sensitive polymers, phase sensitive polymers, pH sensitive polymers, and photosensitive polymers. See, for example, K. Al-Tahami and J. Singh "Smart Polymer Based Delivery Systems for Peptide and Proteins", Recent Patents on Drug Delivery & Formulation, 1: pages: 65-71 Bentham Science Publishers, LTD. 2007.

US Patent No. 6,592,899 describes a PLA/PLGA oligomer combined with a block copolymer to increase the solubility of a hydrophobic drug in a hydrophilic environment. More specifically, this polymer composition has a polyester oligomer having a molecular weight between 400 and 10,000 daltons and an AB type, ^a B ^a type or BAB type biodegradable block copolymer. The hydrophobic part A is a polyester, while the hydrophilic part B is a polyethylene glycol having a molecular weight between 2,400 and 4,999 daltons. This polymer composition is soluble in an aqueous environment.

US Patent No. 6,541,033 describes a sustained release pharmaceutical composition based on thermosensitive, biodegradable hydrogels, consisting of a block copolymer of PLA or PLGA and PEG, for the sustained release of biologically active agents, such as leptin. Sustained release occurs over a period of one week or greater and preferably up to one month.

Hydrogels containing triblock copolymers are described in US Patent No. 6,350,812. These hydrogels retain a weight of water at least equal to the weight of water in the copolymer and are soft hydrogels.

US2005/112170 A1 discloses biodegradable drug-releasing compositions comprising a di-block copolymer, tri-block copolymer or mixture of di- and tri-block copolymers, both comprising a 500-30000 PEG block. Da and a block of poly(lactic acid) of 1500-7500 Da.

The biodegradable drug compositions of the present invention comprise triblock copolymers and diblock copolymers formulated in such a way that the diblock copolymer serves as a reservoir while the triblock copolymer acts as a framework in formulations and increases shelf life. of the diblock copolymer.

In addition, the biodegradable drug-releasing compositions of the present invention can be long-acting formulations, which reduce the initial burst release of the drug and modulate the rate of drug release over time. This phenomenon is illustrated by the flattening of the drug release curves.

Summary of the invention

The present invention provides a biodegradable drug release composition comprising (a) a biodegradable triblock copolymer having the formula:

A ^v - B ^w -A ^x

wherein A is a polyester, specifically polylactic acid, and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

Cy-Az

wherein A is a polyester, specifically polylactic acid, and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the proportion of copolymer of the biodegradable triblock of (a) and the biodegradable CA diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

The present invention provides a biodegradable drug release composition comprising (a) a biodegradable triblock copolymer having the formula:

A ^v - B ^w -A ^x

wherein A is a polyester, specifically polylactic acid, and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

Cy-Az

wherein A is a polyester, specifically polylactic acid, and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371, wherein the proportion of biodegradable triblock copolymer of ( a) and the biodegradable CA diblock copolymer of (b) is from 1:3 to 1:8 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

The present invention provides a biodegradable drug release composition comprising (a) a biodegradable triblock copolymer having the formula:

A ^v -B ^w -A ^x

wherein A is a polyester, specifically polylactic acid, and B is polyethylene glycol and v, w, and x are the number of repeat units ranging from 4 to 1090, with v and x being ester repeat units and w being oxide repeat units of ethylene y v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

C ^{y -Az}

wherein A is a polyester, specifically polylactic acid, and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237 or 7 to 371, where y is the number of repeat units ethylene oxide repeat and z the number of ester repeat units, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is from 1:1 to 1:19 or from 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

The present invention provides a biodegradable drug release composition comprising (a) a biodegradable triblock copolymer having the formula:

A ^v -B ^w -A ^x

wherein A is a polyester, specifically polylactic acid, and B is polyethylene glycol and v, w, and x are the number of repeat units ranging from 6 to 1090, with v and x being ester repeat units and w being oxide repeat units of ethylene y v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

C ^y -A ^z

wherein A is a polyester, specifically polylactic acid, and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371, where y is the number of repeat units of ethylene oxide and z the number of ester repeat units, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is from 1:3 to 1:8 in said biodegradable drug composition. ; and (c) at least one pharmaceutically active ingredient.

A biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 4 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

PEG ^y -PLA ^z

where ze and y are the number of repeat units ranging from 3 to 237 or 3 to 371, where the proportion of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:6 in said biodegradable drug composition and wherein the PEG in the diblock is end-capped; and (c) at least one pharmaceutically active ingredient.

A biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v - PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

PEG ^y -PLA ^z

wherein z and y are the number of repeat units ranging from 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:6 in said composition biodegradable drug and in which the PEG in the diblock is protected at its end; and (c) at least one pharmaceutically active ingredient.

Further in another aspect there is provided a biodegradable drug release composition, comprising: (a) a biodegradable triblock copolymer present in an amount of 2.0% to 45% (wt%/wt%) of the total composition that has the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w, and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer present in an amount of 8.0% to 50% (wt%/wt%) of the total composition having the formula:

PEG ^y -PLA ^z

where z and y are the number of repeat units ranging from 3 to 237, where the ratio f of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:4 or 3 :2 to 1:19 or 1:1 to 1:19 in said biodegradable drug composition and wherein the PEG in the diblock is end-capped and (c) at least one pharmaceutically active substance is present in an amount from 1% to 20% (% by weight/% by weight) of the total composition or the at least one pharmaceutically active ingredient is present in an amount of 1 to 200 mg/ml.

Further in another aspect there is provided a biodegradable drug release composition, comprising: (a) a biodegradable triblock copolymer present in an amount of 3.0% to 45% (wt%)/wt% of the total composition that has the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer present in an amount of 8.0% to 50% (wt%/wt%) of the total composition having the formula:

PEG ^y -PLA ^z

wherein z and y are the number of repeat units ranging from 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:4 in said composition of biodegradable drug and in which the PEG in the diblock is capped at its end and (c) at least one pharmaceutically active substance is present in an amount of 1% to 20% (wt%/wt%) of the total composition or the at least one pharmaceutically active substance is present in an amount of 1 to 200 mg/ml.

In another aspect a biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 4 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

mPEG ^y -PLA ^z

where ze and y are the number of repeat units ranging from 3 to 237, where the proportion of the copolymer of biodegradable triblock of (a) and the biodegradable diblock copolymer of (b) is 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

In another aspect a biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v - PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

mPEG ^y -PLA ^z

wherein z and y are the number of repeat units ranging from 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:6 in said composition of biodegradable drug; and (c) at least one pharmaceutically active ingredient.

In another aspect a biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 4 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

mPEG ^y -PLA ^z

where z and y are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1: 4 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

In another aspect a biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

mPEG ^y -PLA ^z

wherein z and y are the number of repeat units ranging from 7 to 371, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1:4 in said composition of biodegradable drug; and (c) at least one pharmaceutically active ingredient.

Biodegradable drug-releasing compositions of the invention may have a molar ratio of lactic acid to ethylene oxide in the composition between 0.5 and 3.5 or 0.5 to 22.3 for the triblock copolymer and between 2 and 6 or from 0.8 to 13 for the diblock copolymer.

In another aspect the biodegradable drug-releasing compositions of the invention may have a molar ratio of lactic acid to ethylene oxide in the composition between 0.5 and 22.3 for the triblock copolymer and between 0.8 and 13 for the diblock copolymer.

Furthermore, in another aspect, the biodegradable drug-releasing compositions of the invention may have a molar ratio of lactic acid to ethylene oxide in the composition between 0.5 and 2.5 for the triblock copolymer and between 3 and 5 for the diblock copolymer.

In one aspect the biodegradable drug-releasing composition is an injectable liquid that when inserted into the body of an animal or plant becomes a hardened implant.

In yet another aspect the biodegradable drug release composition can be used as a spatial formulation so that it can be applied onto or into the body of an animal or plant. For example, it can be administered during surgery to treat a wound or inside a plant to treat a virus.

In another aspect the biodegradable drug composition is prepared in the form of small solid particles, which are placed directly on the injured site of an animal or plant body.

In another aspect the biodegradable drug composition is in the form of a rod-shaped implant.

A method for preparing the biodegradable drug-releasing composition of the invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula:

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 6 to 1090 where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

wherein A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371 in a ratio of 1:3 to 1:8 (a):(b) to form a polymer blend; and

(ii) adding at least one pharmaceutically active principle to said polymer mixture is also another aspect of the invention.

A method for preparing the biodegradable drug-releasing composition of the invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula:

Av-Bw-Ax

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237, where y is the number of ethylene oxide repeat units and z is the number of repeat units of ester in a ratio of 1:1 to 1:19 or 3:2 to 1:19 (a):(b) to form a polymer blend; and

(ii) adding at least one pharmaceutically active principle to said polymer mixture is also another aspect of the invention.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

Av-Bw-Ax

where A is a polyester or and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 6 to 1090 where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

wherein A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371 in a ratio of 1:4 in (a):(b) to form a mixture of polymer; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

Av-Bw-Ax

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237 in a ratio of 1:1 to 1:19 or 3:2 to 1:19 (a):(b) to form a mixture of polymer; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 6 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371, where y is the number of ethylene oxide repeat units and z is the number of repeat units of ester, in a ratio of 1:4 (a):b) to form a polymer blend; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

A ^v -B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237, where y is the number of ethylene oxide repeat units and z is the number of repeat units of ester, in a ratio of 1:4 (a):(b) to form a polymer blend; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

In the aforementioned methods the organic solvent may be present in an amount of 40% to 74% (wt%/wt%) of the total composition. Solvent mixtures can also be used.

Other aspects and embodiments are presented below, or will readily arise from the following exception to the preferred embodiments.

Brief description of the figures

FIGURE 1 is a graph showing the in vitro drug release rate from formulations based on 40% P6R1(TB):dP2R4(DB) in ratios of 1:0 (-o-), 1:2 (-A-), 1:4 (-•-), 1:6 (-▼-) and 1:9 (-*-) in time in days. This graph shows that TB:DB-based formulations maintain release for more than 30 days.

FIGURE 2 is a graph showing the in vitro cumulative percentage release curve of the candidate formulations of Figure 1 over time (days). This graph illustrates that the initial burst is reduced and the drug release curve is flattened in the combination of the triblock copolymer and diblock copolymer compositions compared to the triblock copolymer composition alone. It should be noted that the 1:9 curve overlaps the 1:4 curve.

FIGURE 3 is a graph showing the injectability of formulations based on 40% P6R1(TB);dP2R4(DB) in various ratios ranging from triblock copolymer to diblock copolymer to 1:0 to diblock copolymer. triblock copolymer to diblock copolymer at 0:1. This graph illustrates that all the formulations are injectable using a classical injection device.

FIGURE 4 is a graph showing the in vitro cumulative percentage release curve of candidate formulations over time (days) of various compositions of the invention. The compositions described under the numbers 177, 246, 224, 225 and 250 are described in Table 1.

FIGURE 5 is a graph showing the in vitro release rate of candidate formulations in micrograms per hour per gram of formulation (|jg/h/g of formulation) Compositions described as 177, 246, 224, 225 and 250 are described in Table 1.

FIGURE 6 is a graph showing the plasma concentration of M53 in nanograms per milliliter (ng/ml) over time in days. The traveler is the day the composition was administered subcutaneously. The compositions indicated with the numbers 177, 246, 224, 225 and 250 are described in Table 1.

FIGURE 7 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.2R5 triblock copolymer (4 ethylene oxide units and 24 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 8 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.2R14 triblock copolymer (4 ethylene oxide units and 58 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 9 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.2R22 triblock copolymer (4 ethylene oxide units and 89 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 10 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.4R4 triblock copolymer (9 ethylene oxide units and 41 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 11 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.4R7 triblock copolymer (9 ethylene oxide units and 67 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 12 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.6R1 triblock copolymer (13 ethylene oxide units and 26 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 13 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.6R3 triblock copolymer (13 ethylene oxide units and 40 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 14 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P0.6R4 triblock copolymer (13 ethylene oxide units and 55 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 15 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P1R2 triblock copolymer (22 ethylene oxide units and 47 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 16 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P1R3 triblock copolymer (22 ethylene oxide units and 68 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 17 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P1R4 triblock copolymer (22 ethylene oxide units and 88 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 18 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R2 triblock copolymer (45 ethylene oxide units and 88 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 19 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R3 triblock copolymer (45 ethylene oxide units and 157 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 20 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R5 triblock copolymer (45 ethylene oxide units and 216 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 21 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P3R1 triblock copolymer (68 ethylene oxide units and 66 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 22 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P3R2 triblock copolymer (68 ethylene oxide units and 154 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 23 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P3R3 triblock copolymer (68 ethylene oxide units and 218 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 24 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P6R0.9 triblock copolymer (136 ethylene oxide units and 125 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 25 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P6R1.6 triblock copolymer (136 ethylene oxide units and 218 lactic acid units). mixed with various diblock copolymers (for details see Table 2).

FIGURE 26 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P6R2 triblock copolymer (136 ethylene oxide units and 272 lactic acid units) mixed with various diblock copolymers (for details see Table 2).

FIGURE 27 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R4 triblock copolymer (45 ethylene oxide units and 157 lactic acid units) mixed with the diblock copolymer dP0.4R6 (7 ethylene oxide units and 42 lactic acid units) in different proportions (for details see Table 2).

FIGURE 28 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R4 triblock copolymer (45 ethylene oxide units and 157 lactic acid units) mixed with the diblock copolymer dP0.6R5 (12 ethylene oxide units and 54 lactic acid units) in different proportions (for details see Table 2).

FIGURE 29 is a graph showing the percentage in vitro cumulative release of acetaminophen over time (days) from formulations based on the P2R5 triblock copolymer (45 ethylene oxide units and 216 lactic acid units) mixed with the diblock copolymer dP0.2R13 (3 ethylene oxide units and 39 lactic acid units) in different proportions (for details see Table 2).

FIGURE 30 is a graph showing the in vitro release rate of buprenorphine over time (days) of formulations #33 (10% BN/8% P2R2/32% dP0.4R10), no. #47 (10% BN/8% P2R2/32% dP1R3) and #58 (10% BN/10% P0.4R8/40% dP1R2).

FIGURE 31 is a graph showing the plasma concentration of buprenorphine over time (days) in rats injected with formulations #33 (10% BN/8% P2R2/32% dP0.4R10), n #47 (10% BN/8% P2R2/32% dP1R3) and #58 (10% BN/10% P0.4R8/40% dP1R2).

FIGURE 32 is a graph showing the in vitro release rate of risperidone over time (days) from formulations based on the P2R5 triblock polymer (45 ethylene oxide units and 216 lactic acid units) mixed with the diblock polymer dP0.2R13 (3 ethylene oxide units and 39 lactic acid units) at different proportions (for details see Table 2).

FIGURE 33 is a graph showing the plasma concentration of risperidone and 9-OH risperidone over time (days) in rats injected with formulations #10 (5% RSP/16% P2R2/24 dp2R2 %/ DMSO), #29 (10% rSp/24% P1R4/16% dP0.4R5/DMSO) and #31 (10% RSP/18% P2R4/dP0.4R5 12% / DMSO).

FIGURE 34 is a graph showing the plasma concentration of ivermectin over time (days) in dogs injected with formulations #7 (5% IVM/15% P3R3/25% dP0.4R5/DMSO). , #9 (5% IVM/15% P2R4/25% dP2R3/DMSO) and #10 (5% IVM/15% P2R5/25% dP2R2/DMSO).

Description of the preferred embodiments

As used herein the term "biodegradable" refers to the fact that triblock and diblock copolymers will erode or degrade after a period of time in vivo to form smaller non-toxic components.

The term "parental administration" includes intramuscular, intraperitoneal, intra-abdominal, subcutaneous, intravenous, and intra-arterial. It also includes intradermal, intracavernous, intravitreal, intracerebral, intrathecal, epidural, and intraosseous administration.

The term "animals" includes all members of the Animal Kingdom. As used herein the term "plant" includes all members of the Plant Kingdom.

"Active ingredient" refers to a drug or medicine for the treatment of various medical conditions. Therefore, active principles, drugs and medicines are used interchangeably. The term drug or active ingredient as used herein includes, but is not limited to, physiologically or pharmacologically active substances that act locally or systemically in the body of an animal or plant. At least one active principle is present in the biodegradable drug composition of the invention.

As used herein "disease" refers to any disorder in a human, animal, or plant caused by infection, diet, or process malfunction.

The term "implant" means that the drug-releasing compositions are injectable, form in situ , and are biodegradable and become solid implants when injected into the body. Therefore, the formulations that are synthesized are liquid so that they can be easily injected through a syringe without excessive force. The expression "space formulations" includes any formulation that can be applied on or in the body of an animal or plant and its administration need not be carried out through a syringe.

As used herein "repeating units" are the fundamental recurring units of a polymer.

By "end-capped polyethylene glycol" (cPEG) is meant those PEGs in which a terminal hydroxyl group reacts and includes alkoxy-protected PEGS, urethane-protected PEGs, ester-protected PEGs, and the like. The protecting group is a chemical group that does not contain a chemical functional group capable of reacting with cyclic esters such as lactide, glycolactide, caprolactone and the like, and there were other esters and mixtures thereof. Reaction of a PEG polymer endcapped with lactide generates a diblock cPEG-PLA copolymer. As used herein polyethylene glycol, abbreviated as PEG throughout the application, is sometimes referred to as poly(ethylene oxide) or poly(oxyethylene) and the terms are used interchangeably herein.

The abbreviation "PLA" refers to poly(lactic acid).

The abbreviation "PLGA" refers to poly(lactic-co-glycolic acid).

The abbreviation "T" or "TB" refers to a triblock copolymer(s), while the abbreviation "D" or "DB" refers to a diblock copolymer(s).

The term "diblock" as used herein refers, for example, to an end-capped PEG-polyester copolymer. "mPEG" refers to methoxy polyethylene glycol.

The term "triblock" refers, for example, to a polyester-PEG-polyester copolymer.

The LA/EO ratio refers to the molar ratio of lactic acid units to ethylene oxide units that is present in the biodegradable drug-releasing composition. It is determined experimentally by NMR. The LA/eO ratio of the combined triblock copolymer can vary from 0.5 to 3.5. In another aspect, the LA/EO molar ratio in the triblock can range from 0.5 to 2.5 in the biodegradable drug-releasing composition described herein. Furthermore, in another aspect the ratio of LA/EO in the triblock which can vary from 0.5 to 22.3.

The LA/EO ratio in the diblock can range from 2 to 6. In another aspect the LA/EO ratio in the diblock can range from 3 to 5 in the biodegradable drug-releasing composition. In another aspect the ratio of LA/EO in the diblock can vary from 0.8 to 13.

The degree of polymerization or DP is the number of repeating units in a polymer chain of average size at time t in a polymerization reaction. For example, the degree of polymerization for PEG is about 45 to 170 or it can be 4 to 273 or 3 to 45, while for PLA it can range from about 84 to 327 or it can be 24 to 682 or 7 to 327.

Therefore, the present invention relates to a biodegradable drug composition comprising a triblock copolymer and a diblock copolymer. The biodegradable triblock copolymer has the formula: A ^v -B ^w -A ^x , where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging, for example, from 4 to 1090 or from 6 to 1090 and v = xovt x. w is the degree of polymerization (number of repeat units) for PEG. The degree of polymerization for DP-PEG is calculated by dividing the molecular weight of the PEG by the molecular weight of the EO unit (44 Da). vx is equal to the degree of polymerization (number of repeat units) for PLA. DP-PLA is calculated by multiplying DP-PEG by the LA/EO ratio.

However, the number of v, w and x repeat units in the triblock composition may vary due to the targeted release time of the active substance and the type of active substance itself. Therefore, the number of repeat units in the triblock of v, w, and x can vary from 8 to 1090, from 10 to 850, from 20 to 700, from 30 to 650, and v = x or v t x. For example, w can be 273, while x y can be 682 and v = x or v t x or w can be 136 and x y can be 273 and v = x or v t x or w can be 45.5 and x y can be 546 or w can be 273 and x y can be 136.

The PEG size in the triblock can range from 194 Da to 12,000 Da.

The polyester in the triblock that is used can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester that is used is polylactic acid.

The triblock copolymer is then combined with a biodegradable diblock copolymer having the formula: C ^y -A ^z , where A is a polyester and C is an end-capped polyethylene glycol y z and y are the number of repeat units that range from 7 to 371 or 3 to 327. This combination has a ratio of triblock copolymer to diblock copolymer ranging from 1:3 to 1:8 or 1:1 to 1:19 or 3:2 at 1:19.

Examples of end-capped polyethylene glycols include alkoxy-protected PEGs such as methoxyPEG or ethoxyPEG, urethane-protected PEGs, ester-protected PEGs, amino-protected PEGs, and amido-protected PEGs. The listing of capped PEGs is not exhaustive and a person skilled in the art could recognize additional capped PEGs, which are not listed.

However the number of repeating units (degree of polymerization (DP)) of zey in the diblock composition can also vary. So, y can range from, for example, 7 to 43 or 3 to 45 and z can range from 32 to 123 or 7 to 327. For example, y can be 25 and z can be 123, y can be 34, 5 and z can be 123 or y can be 45 and z can be 32. The degree of polymerization for DP-PEG is calculated by dividing the PEG molecular weight of the capped PEG by the molecular weight of the EO unit (44 Da). The ^dP -PLA is calculated by multiplying DP-PEG by the LA/EO ratio.

The polyester in the diblock can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester that is used is polylactic acid. In another embodiment, the polyester is poly(lactic-co-glycolic acid).

In another aspect the present invention provides a biodegradable drug release composition comprising (a) a biodegradable triblock copolymer having the formula:

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w, and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units y v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

C ^{y -Az}

where A is a polyester and C is an end-capped polyethylene glycol yz and y are the number of repeat units ranging from 7 to 371 or 3 to 237, where y is the number of ethylene oxide repeat units and z is the number of ester repeat units, wherein the ratio of biodegradable triblock copolymer from (a) and biodegradable ^cA diblock copolymer from (b) is 1:3 to 1:8 or 1:1 to 1 :19 or from 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

In another aspect the present invention provides a biodegradable drug release composition comprising a biodegradable triblock copolymer having the formula: PLA ^v -PEG ^w -PLA ^x , where v, w and x are the number of repeat units that they vary from 4 to 1090 or from 6 to 1090 and v = xovtx; a biodegradable diblock copolymer having the formula: mPEG ^y -PLA ^z , where ze and y are the number of repeat units ranging from 7 to 371 or 3 to 327, where the ratio of the biodegradable triblock copolymer and the biodegradable diblock copolymer is 1:6 in said biodegradable drug composition; and at least one pharmaceutically active ingredient.

In another aspect a biodegradable drug release composition comprises: (a) a biodegradable triblock copolymer having the formula:

PLA ^v -PEG ^w -PLA ^x

where v, w, and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula:

mPEG ^y -PLA ^z

where z and y are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 1: 4 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient.

The ratio of the biodegradable triblock copolymer from (a) and the biodegradable CA diblock copolymer from (b) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition. In one embodiment the ratio of the biodegradable triblock copolymer and the biodegradable CA diblock copolymer is selected from the group of 1:3, 1:4, 1:5, 1:6, 1:7 and 1:8 or 1: 1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, and 1:19. It can also be 3:2. In another aspect the ratio of the triblock to the diblock is 1:6.

The length of the polyester chain is defined by its molar ratio of polyester to ethylene oxide, which is between 0.5 and 3.5 or 0.5 to 2.5 or 0.5 to 22, 3 for the triblock copolymer and 3 to 5 or 2 to 6 or 0.8 to 13 for the diblock copolymer. Thus, for example, if polylactic acid is used, the chain length is defined by the lactic acid/ethylene oxide molar ratio. Similarly, if polyglycolic acid is used, the chain length is defined by the polyglycolic acid/ethylene oxide molar ratio or the polycaprolactone/ethylene oxide molar ratio or the olihydroxyalkanoate/ethylene oxide molar ratio. If poly(lactic-co-glycolic) acid is used the chain length is defined by the ratio of LA G/EO.

The mass of the capped polyethylene glycol can range from 164 Da to 2,000 Da or from 100 Da to 2 kDa. It can vary in the lower range of 100 to 300 Da or in the range of 1 kDa to 2 kDa.

The size of the polyethylene glycol chain ranges from 200 Da to 12 kDa in the biodegradable drug-releasing composition or may range from 400 Da to 12 kDa or 194 Da to 12 kDa.

The polymers are present in an amount of 20% to 50% (wt%/wt%) of the total weight of the composition. In another aspect, the total weight of the former present in the biodegradable drug composition is from 30% to 50% (% by weight/% by weight) of the total weight of the composition. In yet another aspect polymers are present in the biodegradable drug composition from 40% to 50% (wt%/wt%) of the total weight of the composition.

Thus, the triblock copolymer is present in an amount of 3.0% to 45% (wt%/wt%) of the total weight of the composition. In another aspect the triblock copolymer is present in an amount of 6% to 10% (wt%/wt%) of the total weight of the composition. Furthermore in another aspect the triblock copolymer is present in an amount of 20% to 40% (wt%/wt%) of the total weight of the composition.

Likewise, the diblock copolymer may be present in the biodegradable drug composition in an amount of 8% to 50% (wt%/wt%) of the total weight of the composition. In another aspect the diblock copolymer is present in an amount of 10% to 20% (wt%/wt%) of the total weight of the composition. Furthermore in another aspect the diblock copolymer is present in an amount of 20% to 40% (wt%/wt%) of the total weight of the composition.

The at least one pharmaceutically active ingredient is entrapped in the biodegradable triblock:diblock drug-releasing composition. Representative drugs and biologically active agents to be used in the invention include, but are not limited to, peptide drugs, protein drugs, desensitizing agents, antigens, vaccines, vaccine antigens, anti-infective agents, antibiotics, antimicrobial agents, antiallergenic agents, anti-diabetic agents, steroidal anti-inflammatory agents, decongestant agents, miotics, anticholinergics, sympathomimetics, sedatives, hypnotics, psychic energizers, tranquilizers, androgenic steroids, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, corticosteroids, antispasmodics, antimalarials, antihistamines, cardioactive agents, nonsteroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, beta-adrenergic blocking agents, nutritional agents, gonadotropin-releasing hormone agonists, insecticides, anti-helminth agents, and the benzophenanthridine alkaloids.

Therefore, combinations of drugs can also be used in the biodegradable drug-releasing composition of the present invention. For example, if it is necessary to treat Lupus erythematosus, non-steroidal anti-inflammatory agents and corticosteroids can be administered together in the present invention.

Veterinary medicines such as medicines for the treatment of worms or vaccines for animals also form part of the present invention.

Also included in the present invention are plant viral medicines such as viruses of Potyviridae, Geminiviridae, Bunyaviridiae genus Tospovirus and Banana streak virus. Medicines for tobacco mosaic virus, turnip wrinkle virus, barley yellow dwarf, watermelon ringspot and cucumber mosaic virus can also be used in the biodegradable drug-releasing composition of the invention.

For those skilled in the art, other drugs or biologically active agents that can be delivered in an aqueous environment can be used in the described delivery system. In addition, various forms of the drugs or biologically active agents can be used. These include, but are not limited to forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologically activated when injected into the animal or plant or used as a spatial formulation so which can be applied on or within the body of an animal or plant or as a rod-shaped implant.

The pharmaceutically effective amount of an active ingredient can vary depending on the active ingredient, the extent of the medical condition of the animals or plants, and the time required to release the active ingredient. There is no critical upper limit on the amount of active ingredient incorporated into the polymer solution except for that of an acceptable solution or dispersion viscosity for injection through a syringe needle and that can effectively treat the medical condition. without subjecting the animal or plant to an overdose. The lower limit of the active principle incorporated in the delivery system simply depends on the activity of the active principle and the period of time necessary for the treatment.

For example, some active ingredients may be present in the biodegradable drug-releasing composition at 10 to 200 mg/ml. In another aspect, the drugs should be present in the amount of 10 to 40 μg/ml. For a small molecule, for example, the active principle can be loaded in an amount as high as 100 to 200 mg per ml.

Generally, the pharmaceutically active ingredient is present in an amount of from 1% to 20% (wt%/wt%) of the total weight of the composition. In another aspect, the active ingredient is present from 1% to 4% (wt%/wt%) of the total weight of the composition. In another aspect, the active principle is present from 2% to 4% (wt%/wt%) of the total weight of the composition. Furthermore, in another aspect, the active principle, which is a small molecule, is present in an amount of 10% to 20% (wt%/wt%) of the total weight of the composition.

In the biodegradable drug-releasing composition of the present invention, the pharmaceutically effective amount can be gradually released over a long period of time. This slow release can be continuous or discontinuous, linear or non-linear, and can vary due to the composition of the triblock copolymer and diblock copolymer. Therefore, the higher the lactic acid content of the triblock and diblock copolymers compared to the polyethylene glycol content, as well as the amount of triblock and diblock copolymers present in the biodegradable drug composition, the higher the release of the drug. active substance or drug. In other words, the higher the LA/EO molar ratio and the higher the weight percentage of the triblock and diblock copolymers, the longer the period of time will be required for the active ingredient to be released from the drug composition.

The active principle can be released for a period of time between 7 days and 1 year or a longer period depending on the type of treatment needed and the biodegradable drug-releasing composition used. In one aspect the biodegradable drug release composition can release the active ingredient for at least 7 days. In another aspect the biodegradable drug release composition can release the active ingredient for at least 30 days. In one aspect the biodegradable drug release composition can release the active ingredient for at least 90 days. In yet another aspect, the biodegradable drug release composition must release an active ingredient for 1 year or longer.

The biodegradable drug-releasing composition may be a liquid injectable at room temperature and may be injected via syringe without undue force. But these biodegradable drug-releasing compositions also form in situ and are biodegradable and become solid implants when injected into the animal or plant. Alternatively, the biodegradable drug composition is produced as a solid, prepared as small particles, and used as a powder to be dusted on the injured site. In another aspect, the drug-releasing composition is a rod-shaped implant, which can be implanted under the skin or in another compartment in the body. In another aspect, the drug release composition can be prepared and applied as a film. In yet another aspect the biodegradable drug-releasing composition can be used as a spatial formulation so that it can be applied on or within the body of an animal or plant. It can be applied anywhere on the body, including the eye.

The biodegradable drug-releasing composition may further comprise a pharmaceutically acceptable excipient, adjuvant or vehicle. An acceptable vehicle can be saline, buffered saline, and the like. It can be added to the biodegradable drug-releasing composition after its formulation with the drug and diblock copolymer and triblock copolymer.

The adjuvant can be formulated simultaneously when the drug is mixed. In this regard, adjuvants that can be used are alum, aluminum phosphate, calcium phosphate, MPL™, CpG motifs, modified toxins, saponins, endogenous stimulatory adjuvants such as cytokines, Freund's complete and incomplete adjuvants, ISCOM type adjuvants , muramyl peptides and the like.

The vehicle can be any diluent, additional solvent, filler or binder that can alter the release of the active ingredient when necessary in the biodegradable drug-releasing composition. Examples include small amounts of triglycerides such as triacetin or tripropionin. The amount that can be used in the present biodegradable drug-releasing compositions of the present invention can range from 12% to 20% (wt%/wt%). In one aspect in the formulation a triacetin may be added at 17.0% (wt%/wt%). In another aspect, tripropionin (abbreviated herein as Tripro) may be added at 16% (wt%/wt%).

Also included in the invention is a method for preparing the biodegradable drug-releasing composition of the invention. This method comprises: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: A ^v -B ^w -A ^x , where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable diblock copolymer having the formula: C ^y -A ^z , where A is a polyester and C is an end-capped polyethylene glycol and ze and are the number of repeat units ranging from 7 to 371 or from 3 to 237 in a ratio of 1:3 to 1:8 or 1:1 to 1:19 or 3.2 to 1:19 triblock to diblock to form a polymer blend; and adding at least one pharmaceutically active ingredient to said polymer mixture.

A method for preparing the biodegradable drug-releasing composition of the invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula:

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w, and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371 or 3 to 237, where y is the number of ethylene oxide repeat units and z is the number of ester repeat units, in a ratio of 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 (a):(b) to form a polymer blend ; and (ii) adding at least one pharmaceutically active ingredient to said polymer mixture is yet another aspect of the invention.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090 where v = x or v t x; and (b) a biodegradable diblock copolymer having the formula:

Cy-Az

wherein A is a polyester and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371 or 3 to 137 in a ratio of 1:4 (a:b) to form a polymer blend; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

Further another aspect of the present invention provides a method for preparing the biodegradable drug-releasing composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula :

A ^v - B ^w -A ^x

where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 6 to 1090, with v and x being ester repeat units and w being ethylene oxide repeat units where v = x or v t x; and(b) a biodegradable diblock copolymer having the formula:

Cy-Az

where A is a polyester and C is an end-capped polyethylene glycol and z and y are the number of repeat units ranging from 7 to 371 or 3 to 237, where y is the number of ethylene oxide repeat units and z is the number of ester repeat units, in a ratio of 1:4 (a):b) to form a polymer blend; (ii) adding at least one pharmaceutically active ingredient to said polymer mixture; and (iii) evaporating said solvent.

Another embodiment provides a method for preparing the biodegradable drug-releasing composition of the invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: A ^v -B ^w -A ^x , where A is a polyester and B is polyethylene glycol and v, w and x are the number of repetition units that vary from 4 to 1090 or from 6 to 1090; and (b) a biodegradable diblock copolymer having the formula: C ^y -A ^z , where A is a polyester and C is an end-capped polyethylene glycol and ze and are the number of repeat units ranging from 7 to 371 or from 3 to 237 in a 1:6 ratio of triblock to diblock to form a polymer blend; adding at least one pharmaceutically active ingredient to said polymer mixture; and evaporating said solvent. In this regard, there is no solvent present in the biodegradable drug release composition.

The organic solvent that can be used in the method described herein is selected from the group of: benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether (Diglima), diethylene glycol monoethyl ether (DEGMEE), dimethyl isosorbide (DMI), Dimethyl Sulfoxide (DMSO), Ethyl Acetate, Ethyl Benzoate, Ethyl Lactate, Ethylene Glycol Monoethyl Ether Acetate, Glycerol Formal, Methyl Ethyl Ketone, Methyl Isobutyl Ketone, N-ethyl-2-pyrrolidone, N- methyl-2-pyrrolidone (NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin (tripro), or triethylene glycol dimethyl ether (triglyme), and mixtures thereof.

The organic solvent is present in an amount of 40% to 74% (wt%/wt%) of the total composition. In another aspect, the organic solvent used in the preparation of the biodegradable drug-releasing composition is present in an amount of 50% to 60% (wt%/wt%) of the total composition. Furthermore in another aspect the solvent used in the preparation of the biodegradable drug-releasing composition is present in an amount of 60% to 70% (wt%/wt%) of the total composition.

Some mPEG-OH are contaminated with a small amount of OH-PEG-OH. Following the methods of the present invention and using the contaminated mPEG-OH, the final product could be a mPEG-PLA contaminated with a small amount of PLA-PEG-PLA, which is included in the present invention.

Another aspect of the present invention is the use of diblock and triblock copolymers for the preparation of a biodegradable drug composition. In this sense, the biodegradable triblock copolymer has the formula: A ^v -B ^w -A ^x , where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090 and v = xovt x. The polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), or polyhydroxyalkanoate (PHA). In one embodiment, the polyester that is used is poly(lactic) acid.

The triblock copolymer is then blended with a biodegradable diblock copolymer having the formula: C ^y -A ^z , where A is a polyester and C is an end-capped polyethylene glycol y z and y are the number of repeat units that they range from 7 to 371 or from 3 to 237. The polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly(lactic-co-glycolic acid PLGA), or polyhydroxyalkanoate (PHA). In one embodiment, the polyester that is used is poly(lactic) acid.

The ratio of the biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is from 1:3 to 1:8 in said biodegradable drug composition. In one embodiment the ratio of the biodegradable triblock copolymer from (a) and the biodegradable CA diblock copolymer is selected from the group of 1:3, 1:4, 1:5, 1:6, 1:7 and 1 :8. or 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, and 1:19. In another aspect the ratio of the triblock to the diblock is 1:6. It can also be 3:2.

The length of the polyester chain is defined by its molar ratio of polyester to ethylene oxide, which is between 0.5 and 3.5 or 0.5 to 2.5 or 0.5 to 22.3 for the triblock and from 3 to 5 or from 2 to 6 or from 0.8 to 13 for the diblock.

The mass of the capped polyethylene glycol can range from 100 Da to 2 kDa or 164 Da to 2 kDa. It can vary in the range of 100 to 300 Da or in the range of 1 kDa to 2 kDa.

The size of the polyethylene glycol chain ranges from 200 Da to 12 kDa in the biodegradable drug-releasing composition or may range from 400 Da to 12 kDa or 194 Da to 12 kDa.

Various embodiments and/or aspects of the invention have been described. However, it will be understood that various embodiments can be made without departing from the scope of the invention.

examples

Example 1 - Synthesis of polymers

The copolymers were synthesized according to the method described in US Patent No. 6,350,812, with minor modifications. Typically, the required amount of PEG (provides the triblock copolymer) or methoxy-PEG (provides the diblock copolymer) was heated to 65°C and dried under vacuum for 2 hours in a reactor vessel. DL-lactide (corresponding to the target moral ratio of LA/EO) and zinc lactate (1/1000 amount of lactide) were added. First the reaction mixture was dehydrated by three short titers of vacuum/N ² . The reaction mixture was heated to 140 °C and quickly degassed in vacuo. The reaction was carried out for four days at 140 °C with a constant flow of nitrogen (20 kPa).

The reaction was cooled to room temperature and its contents dissolved in acetone and then precipitated with ethanol. The obtained product was subsequently dried under reduced pressure. The final product was characterized by 1H NMR for its lactate content. The PLA-PEG-PLA triblock polymers described herein were labeled PxRy where x represents the PEG chain size in kDa and y is the LA/EO molar ratio. The mPEG-PLA diblock polymers described herein were labeled dPxRy where x represents the PEG chain size in kDa and y is the LA/EO molar ratio.

Example 2 - Preparation of the Specific Formulation for the M53 peptide

The formulations described herein were based on an organic solution of polymers containing, as a drug, the peptide M53, a GLP-1 analogue. Typically, 0.4 grams of polymers, corresponding to a mixture of a diblock copolymer and a triblock copolymer in a defined mass ratio, were dissolved in 0.57 grams of a biocompatible solvent at room temperature overnight with constant magnetic stirring. The solvent was either a single solvent or a combination of solvents. The next day, 20 mg of drug was added to the polymer solution and stirred until completely dissolved. When the drug was not soluble in the solvent, a suspension of the drug in a solution of R0 polymer was obtained. Alternatively, the drug was dissolved or suspended in the biocompatible solvent and the polymer(s) added thereafter. The formulations were loaded into a syringe prior to use.

Example 3 - The formulations that were prepared

The various formulations of Examples 1 and 2 were prepared, which are presented in Table 1 for the M53 peptide.

Table 1

Example 4 - Preparation of acetaminophen formulations

The formulations described herein were based on organic polymer solution prepared as in Example 1, containing, as drug, acetaminophen. Typically, 0.4 grams of polymers, corresponding to a mixture of a diblock copolymer and a triblock copolymer in a defined mass ratio, were dissolved in 0.55 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 50 mg of acetaminophen was added to the polymer solution and stirred until completely dissolved. The formulations were loaded into a syringe prior to use. The composition of the various formulations is shown in Table 2 below, where the solvent used is DMSO. Figures 7 to 26 illustrate the results of these formulations showing all possible combinations of 15 triblock copolymers with 20 diblock copolymers.

T l 2 m r 1 4 1 1 22 27 1 4 4 n m l m r iv

Example 5 - Preparation of the buprenorphine formulations

The formulations described herein were based on organic polymer solution prepared as in Example 1, containing, as drug, buprenorphine. Typically, 0.4 grams of polymers, corresponding to a mixture of a diblock copolymer and a triblock copolymer in a defined mass ratio, were dissolved in 0.5 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 100 mg of buprenorphine was added to the polymer solution and stirred until completely dissolved. The formulations were loaded into a syringe prior to use.

For in vivo experiments three different formulations were selected. The composition of these formulations is shown in Table 3 below. . The formulations were injected subcutaneously into the interscapular space of male rats (200-250 g) at a final dose of 100 mg/kg buprenorphine. Blood samples were drawn periodically and analyzed for buprenorphine concentrations by LC/MS/MS.

The formulations are shown in Table 3 below.

The results of these formulations are illustrated in Figures 30 and 31.

Example 6 - Preparation of risperidone formulations

The formulations described herein were based on organic polymer solution prepared as in Example 1, containing, as drug, risperidone. Typically, 0.4 grams of polymers, corresponding to a mixture of a diblock copolymer and a triblock copolymer in a defined mass ratio, were dissolved in 0.5 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 100 mg of risperidone was added to the polymer solution and stirred. The formulations were loaded into a syringe prior to use.

For in vivo experiments three different formulations were selected. The composition of these formulations is shown in Table 4 below. The formulations were injected subcutaneously into the interscapular space of male rats (300 g) at a final dose of 21 mg/kg risperidone. Blood samples were drawn periodically and analyzed for risperidone and 9-OH risperidone concentrations by LC/MS/MS.

The formulations are shown in Table 4 below.

The results of these formulations are illustrated in Figures 32 and 33.

Example 7 - Preparation of ivermectin formulations

The formulations described herein were based on organic polymer solution prepared as in Example 1, containing ivermectin as drug. Typically, 0.4 grams of polymers, corresponding to a mixture of a diblock copolymer and a triblock copolymer in a defined mass ratio, were dissolved in 0.55 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 50 mg of ivermectin was added to the polymer solution and stirred until completely dissolved. For in vivo experiments three different formulations were selected. The composition of these formulations is shown in Table 5 below. The formulations were injected subcutaneously into the interscapular space of male dogs (10 to 17 kg) at a final dose of 0.6 mg/kg ivermectin. Blood samples were drawn periodically and analyzed for ivermectin concentrations by LC/MS/MS.

The formulations are shown in Table 5.

The results are illustrated in Figure 34.

Example 8 - Injectability of different compositions

Various formulations were tested for injectability using formulations with different ratios of triblock (TB) and diblock (DB). Different solutions in DMSO were prepared based on a mixture of the P6 ^r 1(TB) triblock copolymer and the dP2R4(DB) diblock copolymer.

A 50% wt%/wt% polymer mass/formulation was used in these viscosity experiments. The wt%/wt% triblock to diblock used in this experiment was as follows: 50 wt%: 0 wt%, 45 wt%: 5 wt%, 20 wt%: % by weight, 35% by weight: 15% by weight, 15% by weight: 10% by weight, 25% by weight: 25% by weight, 10% by weight: 15% by weight, 15% by weight: % by weight, 5% by weight: 20% by weight, 5% by weight: 45% by weight and 0% by weight: 50% by weight.

The injectability results are shown in Figure 3.

Example 9 - In vitro Release Assay

100 to 500 mg of formulation were added to 20 to 50 ml of physiological buffer. The physiological buffer used was KRT containing 50 mL Krebs/Ringer/Tris (KRT) buffer at pH 7.4, which is 143 mM Sodium Chloride, 5.1 mM Potassium Chloride, 2.7 mM Calcium Chloride, Sulfate. of 1.34 mM Magnesium, 25 mM Tris-Cl at pH 7.4 and 0.1% sodium azide. After injection, the solvent diffused out of the formulation and the remaining polymer formed a solid biodegradable implant within the aqueous environment.

To maintain sedimentation conditions, to release the drug, the release medium was kept under constant stirring at 180 rpm (Unimax 1010 apparatus, Heidolph) at 37°C. At predetermined time intervals, the media was collected and analyzed by HPLC. The amount of the GLP-1 analog M53 peptide released from the formulation was calculated from a calibration curve. The concentration of M53 ranged from 0 to 5 mg/ml or ranged from 0 to 200 μg/ml.

The results are shown in Figure 4 in Figure 5. Figure 5 illustrates the release rate of formulations 177, 224, 225, 246 and 250 as shown in Table 1, while Figure 4 our cumulative release of the drug from the indicated formulations.

When the GPL-1 analog was incorporated into the polymer solution, it encapsulated within the polymer matrix as it solidified. The drug was then released by diffusion within the matrix or by biodegradation of the matrix.

Example 10 - Pharmacokinetic study

Various formulations were tested in a pharmacokinetic study in rats. Compositions containing 1 mg of drug per animal of formulations 177, 224, 225, 246 and 250, as presented in Table 1, were administered subcutaneously to rats. Blood samples were collected in EDTA tubes at different time points, centrifuged, and plasma from each time point was retained. Plasma samples were analyzed by LC/MS/MS and quantitated for drug content. Results are presented as ng/ml plasma measured over time.

The results of a pharmacokinetic study are shown in Figure 6. . As shown in this Figure, three of the five formulations maintain a plasma concentration greater than 0.1 ng/mL for more than 28 days while providing a moderate initial burst release of drug less than 30 ng/mL.

Example 11 - Blood Glucose Levels

Blood glucose levels with patients suffering from type 2 diabetes are recorded prior to treatment. A control group without treatment is used for this study. Patients of either gender with the condition that they have type 2 diabetes and are between the ages of 35 and 60 are used in this study.

A GPL-1 analogue is formulated according to Examples 1 and 2 and has the chemical characteristics of number 230 in Table 1. The resulting injectable liquid is then injected into several patients at a dosage of 8 mg/ml. . The control group is administered PBS.

The amount of blood sugar and fructosamine levels are then measured over a 30-day period, twice a week, before meals and 2 hours after meals. Blood glucose amounts after treatment are measured and the results are averaged. The values are shown in Table 6:

Table 6

Normal results for glucose levels before meals range from 80 to 120 mmol/l. Normal results for glucose levels after meals should be 160 mmol/l or less. Normal fructosamine levels are below 265. Between 265 and 280 indicates excellent blood glucose control; 280 and 500 indicates good blood glucose control; between 320 and 340 indicates fair blood glucose control; and above 350 indicates poor blood glucose control.

Patient 4 was administered the placebo.

These results show that when administered, the biodegradable drug-releasing compositions of the present invention are effective in treating type 2 diabetes.

While the invention has been described in terms of various preferred embodiments, one skilled in the art will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the scope thereof. Accordingly, it is proposed that the scope of the present invention be limited by the scope of the claims.

Claims (18)

1. A biodegradable drug release composition characterized in that it comprises: (a) a biodegradable triblock copolymer having the formula: A ^v - B ^w -A ^x where A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090 and v = x or v t x; (b) a biodegradable diblock copolymer having the formula: Cy-Az wherein A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237 or 7 to 371, wherein the proportion of biodegradable triblock copolymer of (a) and the biodegradable CA diblock copolymer of (b) is 1:3 to 1:8 or 1:1 to 1:19 or 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active ingredient. 2. The biodegradable drug release composition according to claim 1, characterized in that the composition is an injectable liquid at room temperature and forms an implant when injected into the body or are small solid particles or rod-shaped implants or formulations space. 3. The biodegradable drug release composition according to claim 1 or claim 2, characterized in that the polyester is selected from the group of polylactic acid, polyglycolic acid, polycaprolactone, polyethylene adipate, poly(lactic-co-glycolide) ) and polyhydroxyalkanoate. 4. The biodegradable drug release composition according to any of claims 1 to 3, characterized in that the ratio of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is selected from the group of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12 , 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, and 1:19 or 3:2. 5. The biodegradable drug release composition according to any of claims 1 to 4, characterized in that the size of the polyethylene glycol chain varies from 200 Da to 12 kDa or from 194 Da to 12 kDa and the size of the capped polyethylene glycol ranges from 100 Da to 2 kDa or 164 to 2 kDa. 6. The biodegradable drug release composition according to any of claims 1 to 5, characterized in that it further comprises a pharmaceutically acceptable vehicle. 7. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the at least one pharmaceutically active ingredient is present in an amount of 1% to 20% (% by weight/% by weight) of the total composition. 8. The biodegradable drug release composition according to any of claims 1 to 7, characterized in that the polymers are present in an amount of 20% to 50% (wt%/wt%) of the total composition; and/or wherein the tri-block copolymer is present in an amount of from 3.0% to 45% (wt%/wt%) of the total composition; and/or wherein the diblock copolymer is present in an amount of 8.0% to 50% (wt%/wt%) of the total composition. 9. The biodegradable drug release composition according to any of claims 1 to 8, characterized in that the molar ratio of polyester repeat unit to ethylene oxide in the composition is between 0.5 and 3.5 or from 0.5 to 22.3 in the tri-block and from 2 to 6 or from 0.8 to 13 in the di-block. 10. A biodegradable drug release composition according to any of the preceding claims, characterized in that A is PLA, C is mPEG; and wherein the ratio of the biodegradable tri-block copolymer of (a) and the biodegradable di-block copolymer of (b) is 1:6 in the biodegradable drug composition. 11. A biodegradable drug release composition according to any of claims 1 to 9, characterized in that A is PLA, C is mPEG; the biodegradable tri-block copolymer is present in an amount of 3.0% to 45% (wt%/wt%) of the total composition; v, w and x are the number of repeat units ranging from 6 to 1090 and v = x or v t x; the biodegradable di-block copolymer is present in an amount of 8.0% to 50% (wt%/wt%) of the total composition; the ratio of the biodegradable tri-block copolymer of (a) and the biodegradable di-block copolymer of (b) is 1:4 in the biodegradable drug composition; and the at least one pharmaceutically active ingredient present in an amount of 1% to 20% (% by weight/% by weight) of the total composition. 12. The biodegradable drug release composition according to claim 10 or claim 11, characterized in that the composition is an injectable liquid at room temperature and forms an implant when injected into the body or is small solid particles or rod-shaped implants or space formulations. 13. A method for preparing the biodegradable drug release composition according to claim 1 or claim 2, the method characterized in that it comprises: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: A ^v - B ^w -A ^x wherein A is a polyester and B is polyethylene glycol and v, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable diblock copolymer having the formula: Cy-Az where A is a polyester and C is an end capped polyethylene glycol and z and y are the number of repeat units ranging from 3 to 237 or 7 to 371 in a ratio of 1:3 to 1:8 or 1: 1 to 1:19 or 3.2 to 1:19 of (a):(b) to form a polymer blend; and (ii) adding at least one pharmaceutically active principle to said R0 polymer mixture. 14. A method according to claim 13, characterized in that the ratio (a):(b) is 1:6 and wherein the method further comprises (iii) evaporating the solvent. 15. The method according to claim 13 or claim 14, characterized in that the organic solvent is selected from the group of: benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether (Diglima), diethylene glycol monoethyl ether (DEGMEE), Dimethyl Isosorbide (DMI), Dimethyl Sulfoxide (DMSO), Ethyl Acetate, Ethyl Benzoate, Ethyl Lactate, Ethylene Glycol Monoethyl Ether Acetate, Glycerol Formal, Methyl Ethyl Ketone, Methyl Isobutyl Ketone, N-Ethyl-2-Pyrrolidone , N-methyl-2-pyrrolidone (NMP), pyrrolidone-2, tetraglycol, triacetin, tributyrin, tripropionin, or triethylene glycol dimethyl ether (triglyme), and mixtures thereof. 16. The method according to any of claims 13 to 15, characterized in that the organic solvent is present in an amount of 40% to 74% (wt%/wt%) of the total composition. 17. Use of the biodegradable drug release composition according to any of claims 1 to 12, for the preparation of a medicament for treating diseases in animals or plants. 18. A biodegradable drug-releasing composition according to any of claims 1 to 12 for use in medicine.